Article

Current limitations of molecular magnetic resonance imaging for tumors as evaluated with high-relaxivity CD105-specific iron oxide nanoparticles

CT and MR Contrast Media Research, Bayer Pharma AG, Berlin, Germany.
Investigative radiology (Impact Factor: 4.45). 05/2012; 47(7):383-91. DOI: 10.1097/RLI.0b013e31824c5a57
Source: PubMed

ABSTRACT Tumor imaging via molecular magnetic resonance imaging (MRI) that uses specific superparamagnetic iron oxide particles (SPIOs) has been addressed in the literature several times in the last 20 years. To our knowledge, none of the reported approaches is currently used for routine clinical diagnostic evaluation, nor are any in clinical development. This raises questions as to whether SPIO-enhanced molecular MRI is sensitive and specific enough for use in clinical practice. The aim of our preclinical study was to investigate the minimum requirements for obtaining sensitive molecular MRI for use in tumor evaluations under optimal conditions. The well-vascularized F9 teratocarcinoma tumor model, which exhibits high levels of the highly accessible target CD105 (endoglin), was used to compare the accumulation and visualization of target-specific SPIOs by MRI.
Superparamagnetic iron oxide particles were optimized in the following ways: (a) proton relaxivity was increased for higher imaging sensitivity, (b) a coating material was used for optimal loading density of the αCD105 antibody, and (c) binding activity to the target CD105 was increased. Binding activity and specificity were confirmed in vitro using enzyme-linked immunosorbent assay and in vivo using pharmacokinetic and biodistribution studies of 11 F9 teratoma-bearing mice together with micro-autoradiography. CD105 target expression was determined using immunohistochemistry and quantitative enzyme-linked immunosorbent assay. The transverse relaxation rate R2* was quantified by 3.0-T MRI in the tumors, kidneys, and muscles before and up to 60 minutes after injection in 11 mice. The use of [Fe]-labeled SPIOs for all in vivo experiments allowed for the direct correlation of the imaging results with SPIO accumulation.
High-relaxivity αCD105-polyacrylic acid-SPIOs (r2 up to 440 L mmol Fe s) with strong binding activity accumulated specifically in tumors (1.4% injected dose/g) and kidneys (4.1% injected dose/g) in a manner dependent on the target concentration. The accumulation occurred within the first 3 minutes after injection. Visualization of specific SPIOs was accomplished with MRI. In contrast to the successful use of MRI in all examined kidneys (mean ± SEM ΔR2*, 61 ± 11 s), only 6 of 11 tumors (mean ± SEM ΔR2*, 15 ± 7 s) showed a clear signal when compared with the control even though optimal conditions were used.
The accumulation of CD105-specific SPIOs in F9 mouse teratomas was robust. However, visualization of the specifically accumulated SPIOs by MRI was not reliable because of its limited signal detection sensitivity. We postulate that it will be challenging to improve the imaging properties of targeted SPIOs further. Therefore, molecular MRI by targeted SPIOs is currently not suitable for clinical tumor imaging using routinely applicable sequences and field strength.

Download full-text

Full-text

Available from: Ulrich Pison, Aug 30, 2015
0 Followers
 · 
188 Views
  • Source
    • "The increasing interest in nanoparticles (NPs) for various applications has led to significant excitement concerning the potential benefits; however, there is concern over the potential for adverse human health effects. Fe 3 O 4 NPs are an important magnetic material, predominantly in the forms of hematite (Fe 2 O 3 ) and magnetite (Fe 3 O 4 ), that have been used in a wide variety of applications, including magnetocaloric refrigeration, drug delivery, magnetic resonance imaging as a contrast agent, ferrofluids, sensors, fuel cells, magnetic storage media, and catalysis (Gupta and Gupta, 2005; Laurent et al., 2008; Mahmoudi et al., 2011; Dassler et al., 2012). Synthetic Fe 3 O 4 s (E172) with different hues, such as yellow, red, brown, and black, have been used as a coloring agents in the food industry, as permitted by the EU-FDA, US-FDA, and FAO/WHO (Scotter, 2011; WHO, 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of engineered nanoparticles (NPs) across multiple fields and applications has rapidly increased over the last decade owing to their unusual properties. However, there is an increased need in understanding their toxicological effect on human health. Particularly, iron oxide (Fe3O4) have been used in various sectors, including biomedical, food, and agriculture, but the current understanding of their impact on human health is inadequate. In this investigation, we assessed the toxic effect of Fe3O4 NPs on human mesenchymal stem cells (hMSCs) adopting cell viability, cellular morphological changes, mitochondrial transmembrane potential, and cell-cycle progression assessment methodologies. Furthermore, the expression of oxidative stress, cell death, and cell-cycle regulatory genes was assessed using quantitative polymerase chain reaction. The Fe3O4 NPs induced cytotoxicity and nuclear morphological changes in hMSCs by dose and time exposure. Cell-cycle analysis indicated that Fe3O4 NPs altered the cell-cycle progression through a decrease in the proportion of cells in the G0–G1 phase. The hMSC mitochondrial membrane potential loss increased with an increase in the concentration of Fe3O4 NPs exposure. The observed expression levels of the CYP1A, TNF3, TNFSF10, E2F1, and CCNC genes were significantly upregulated in hMSCs in response to Fe3O4 NPs exposure. Our findings suggest that Fe3O4 NPs caused metabolic stress through altered cell cycle, oxidative stress, and cell death regulatory gene expression in hMSCs. The results of this investigation revealed that Fe3O4 NPs exhibited moderate toxicity on hMSCs and that Fe3O4 NPs may have biomedical applications at low concentrations. © 2014 Wiley Periodicals, Inc. Environ Toxicol, 2014.
    Environmental Toxicology 12/2014; DOI:10.1002/tox.22098 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Magnetic resonance imaging (MRI) has now been used clinically for more than 30 years. Today, MRI serves as the primary diagnostic modality for many clinical problems. In this article, historical developments in the field of MRI will be discussed with a focus on technological innovations. Topics include the initial discoveries in nuclear magnetic resonance that allowed for the advent of MRI as well as the development of whole-body, high field strength, and open MRI systems. Dedicated imaging coils, basic pulse sequences, contrast-enhanced, and functional imaging techniques will also be discussed in a historical context. This article describes important technological innovations in the field of MRI, together with their clinical applicability today, providing critical insights into future developments.
    Investigative radiology 10/2012; 47(12). DOI:10.1097/RLI.0b013e318272d29f · 4.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Superparamagnetic Iron Oxide Nanoparticles (SPIONs) were synthesized and coated with pseudopolyrotaxanes (PPRs) and proposed as a novel hybrid nanostructure for medical imaging and drug delivery. PPRs were prepared by addition of α-cyclodextrin rings to functionalized polyethylene glycol (PEG) chain with hydrophobic triazine end-groups. Non-covalent interactions between SPIONs and PPRs led to the assembly of SPIONs@PRs hybrid nanomaterials. Measurements of the (1)H Nuclear Magnetic Resonance (NMR) relaxation times T(1) and T(2) allowed us to determine the NMR dispersion profiles. Comparison between our SPIONs@PRs hybrid nano-compound and the commercial SPION compound, Endorem®, showed a higher transverse relaxivity for SPIONs@PRs. In vitro MRI experiments showed that our SPIONs@PRs produces better negative contrast compared to Endorem® and can be considered as a novel MRI contrast agent.
    Colloids and surfaces B: Biointerfaces 11/2012; 103. DOI:10.1016/j.colsurfb.2012.10.035 · 4.15 Impact Factor
Show more